Hypopituitarism

Background

• Hypopituitarism occurs due to partial or complete failure of the pituitary gland to secrete ≥ 1 of the hormones it produces or stores.
• Causes include pituitary tumors and cysts, nonpituitary tumors compressing the pituitary, traumatic brain injury, pituitary surgery, radiation therapy to the sella, hypophysitis (including immune checkpoint inhibitor-induced hypophysitis and lymphocytic hypophysitis), postpartum hemorrhage (Sheehan syndrome), and subarachnoid hemorrhage.
• Clinical presentation varies with specific hormone deficiency, which may include adrenocortical insufficiency, hypothyroidism, hypogonadism, growth hormone (GH) deficiency, and central diabetes insipidus.
  • Acute hypopituitarism can develop secondary to pituitary apoplexy, acute pituitary inflammation, pituitary surgery, traumatic brain injury, or Sheehan syndrome, and it is associated with high mortality if it is not quickly recognized and treated with glucocorticoids.
    • Presentation of pituitary apoplexy may include a sudden onset of:
      • severe headache (usually retro-orbital)
      • pain and neuro-ophthalmic signs due to increased intrasellar pressure in the pituitary impinging on cranial nerves, leading to cranial neuropathies
      • nausea, vomiting, hypotension, and hyponatremia
    • Mortality is usually secondary to an acute loss of adrenocorticotropin hormone (ACTH) and resulting hypoadrenalism.
  • In most patients, hypopituitarism is a chronic condition with an insidious onset.
    • Clinical presentation is nonspecific and varies by the type and severity of hormonal deficiencies.
    • Many patients with hypopituitarism may initially present with isolated or combined (also known as multiple) deficiencies, including GH deficiency, gonadotropin deficiency, and ACTH deficiency, and then progress to thyroid-stimulating hormone (TSH) deficiency (or TSH deficiency followed by ACTH deficiency).
  • Mass effects of pituitary tumors may lead to headaches, progressive visual impairment, and oculomotor nerve impairment.
  • Hyperprolactinemia may occur either as a result of prolactin secretion from a prolactinoma or among patients with other sellar masses as a result of stalk effect.

Evaluation

• Screen asymptomatic patients for hypopituitarism, including those with pituitary macroadenomas and after moderate-to-severe brain injury, subarachnoid hemorrhage, transsphenoidal surgery, or pituitary radiation therapy.
• Symptoms vary and may suggest a specific hormone deficiency, but combinations of deficiencies can be challenging to identify.
  • Common presentations include GH deficiency (short stature in children), hyperprolactinemia or hypoprolactinemia, female delayed puberty, and hypogonadism in males.
  • Less common presentations include central hypothyroidism, central adrenocortical insufficiency, and central diabetes insipidus.
  • Additional symptoms suggestive of pituitary apoplexy include a sudden onset of severe headache, visual loss, variably depressed sensorium, vomiting, and cranial nerve palsy (cranial nerves III, IV, or VI).
• Definitive diagnosis is primarily biochemical, and tests vary depending upon clinical features suggestive of specific hormone deficiencies.
  • Diagnostic tests to confirm hormonal deficiencies include:
    • basal secretion of pituitary and peripheral hormones in the morning, after the patient has fasted (can be used to diagnose most pituitary hormone deficiencies, except for GH and ACTH deficiency)
    • dynamic hormone stimulation tests if there is suspected GH or ACTH deficiency or if there are unclear results on basal hormone tests
  • Testing for suspected ACTH deficiency
    • Consider measuring basal serum cortisol levels at 8-9 AM as first-line test for diagnosis (Weak recommendation). A basal serum cortisol < 80 nmol/L (3 mcg/dL) suggests adrenal insufficiency (Weak recommendation).
    • Central adrenal insufficiency is most commonly diagnosed using standard-dose and low-dose ACTH stimulation tests.
      • Consider performing a corticotropin (ACTH) stimulation test when morning cortisol values are between 80 nmol/L (3 mcg/dL) and 415 nmol/L (15 mcg/dL) (Weak recommendation). Peak cortisol levels < 500 nmol/L (18.1 mcg/dL) at 30 or 60 minutes indicate adrenal insufficiency.
      • Synthetic ACTH (ACTH 1-24, known as tetracosactide [Synacthen] in Europe or cosyntropin [Cortrosyn] in United States) 250 mcg (standard-dose) IV or intramuscular injection is the most widely used test for adrenal insufficiency.
        • Normal adrenocortical reserve is confirmed if peak cortisol concentrations are > 500-600 nmol/L (18.1-21.7 mcg/dL).
        • Adrenal insufficiency is indicated if peak plasma cortisol level is < 500 nmol/L (18 mcg/dL). This differs from Addison disease (primary adrenal insufficiency), in which basal morning ACTH levels are inappropriately normal or low in patients with central hypoadrenalism.
    • Insulin tolerance test (ITT) is the most reliable test for diagnosis of central adrenal insufficiency, but contraindications may limit its use.
  • Testing for suspected TSH deficiency
    • TSH deficiency can be diagnosed using thyroid function tests.
    • TSH deficiency related to the pituitary gland can be distinguished from primary hypothyroidism, as it presents with an inappropriately low or inappropriately normal TSH level despite low basal serum free/total thyroxine (T4) levels.
  • Testing for suspected gonadotropin hormone deficiency
    • Gonadotropin hormone deficiency can often be diagnosed with a basal hormone test.
    • In women, low serum estradiol coincident with low or inappropriately normal follicle-stimulating hormone and luteinizing hormone levels is reported to be diagnostic in the presence of oligomenorrhea or amenorrhea.
    • In men, measurements of morning serum total testosterone < 10.4 nmol/L (< 300 ng/dL) with low or inappropriately normal gonadotropin concentrations on 2 occasions is reported to be diagnostic of gonadotropin deficiency.
  • Testing for suspected GH deficiency
    • Consider biochemical testing for GH deficiency only when there is a high pretest probability of deficiency, which is indicated if ≥ 1 of the following prescreening criteria are fulfilled:
      • young adults with normal pituitary imaging requiring GH therapy for short stature secondary to diagnosed GH deficiency during childhood
      • a possible cause of pituitary damage, which may include a history of pituitary surgery or radiation therapy for an intrasellar lesion, pituitary hypoplasia, hypothalamic mass or infiltration, head trauma, contact sports injury, or stroke
    • Testing may be unnecessary if ≥ 3 other pituitary hormone deficiencies are present and age-adjusted serum insulin-like growth factor I (IGF-I) is low, since GH deficiency is highly probable.
    • Testing involves biochemical stimulation of GH.
      • An ITT is the gold standard for diagnosis of GH deficiency in adults, but contraindications may limit its use.
      • Alternatives to ITT include glucagon stimulation tests, macimorelin tests, or (if available) arginine plus GH-releasing hormone (GHRH) test.
  • Testing for suspected antidiuretic hormone deficiency
    • No diagnostic gold standard exists for diagnosis of antidiuretic hormone deficiency.
      • A water deprivation test is often used for initial diagnosis and can help identify cases of partial inability to concentrate urine.
      • An adjunct to the water deprivation test may include the use of 3% saline stimulation.
    • Measure serum and urine osmolality simultaneously in patients with polyuria (> 50 mL/kg of body weight in 24 hours or 3.5 L/day in a 70-kg [154-lb] person) (Strong recommendation).
      • Normal results are characterized by a serum osmolality > 295 mOsm/kg, urine osmolarity of about 600 mOsm/kg or higher (urine osmolality to plasma osmolality ratio ≥ 2), and a glucose negative urine dipstick.
      • Diabetes insipidus is confirmed by a plasma osmolality > 295 mOsm/kg with inappropriately hypotonic urine (< 600 mOsm/kg; urine osmolality to plasma osmolality ratio < 2).
• After biochemical confirmation of hormonal deficiencies, magnetic resonance imaging of the hypothalamo-pituitary region may help determine if the cause is due to a tumor or other pituitary lesion.

Management

• Management of hypopituitarism includes:
  • replacement of any hormone deficiencies
  • monitoring and treatment of
    • the underlying cause (such as tumor)
    • other complications of hypopituitarism
• If hypopituitarism is caused by a tumor, treat the underlying cause.
  • Pituitary function may be restored after successful surgical removal of the lesion.
  • Use dopamine agonists for management of prolactinoma (Strong recommendation).
  • Transsphenoidal surgery may be needed for prolactinomas that are unresponsive to medication as well as most other pituitary macroadenomas.
• Management of adrenal insufficiency
  • Treat ACTH deficiency with glucocorticoid hormone replacement therapy using either hydrocortisone or prednisone. Mineralocorticoid replacement is not needed in patients with central hypoadrenalism.
  • In patients who also require thyroid hormone replacement therapy, glucocorticoid replacement should begin before thyroid hormone replacement (rather than the other way around) due to the increased rate of glucocorticoid metabolism caused by thyroid hormone and the subsequent risk of precipitating an acute adrenal crisis.
  • Treat patients with suspected adrenal crisis due to secondary adrenal insufficiency immediately with a hydrocortisone 50-100 mg parenteral injection (Strong recommendation).
  • In patients with pituitary apoplexy, preemptive glucocorticoid therapy is recommended before laboratory diagnosis of acute pituitary insufficiency is established, as adrenal insufficiency is a major cause of mortality (Strong recommendation).
• Management of thyroid hormone deficiency
  • Use levothyroxine in doses sufficient to achieve serum free T4 levels in the mid to upper half of the reference range. Appropriate doses are usually up to 1.6 mcg/kg/day, with dose adjustments based on clinical context, age, and free T4 levels (Strong recommendation).
  • Evaluate patients for adrenal insufficiency before starting levothyroxine therapy. Consider prescribing empiric glucocorticoid therapy in patients starting levothyroxine therapy until there is a definitive evaluation for adrenal insufficiency (Weak recommendation).
• Management of gonadotropin deficiency
  • Use gonadal hormone replacement therapy (estrogen and progestin) in premenopausal women with central hypogonadism, assuming no contraindications are present (Strong recommendation).
  • Consider testosterone replacement for men with central hypogonadism and no contraindications in order to (Weak recommendation):
    • prevent anemia related to testosterone deficiency
    • reduce fat mass
    • improve bone mass density, libido, sexual function, energy levels, sense of well-being, and muscle mass and strength
  • Consider starting testosterone replacement therapy at the normal age for puberty onset (11.5-12.5 years) in adolescent boys with hypogonadism.
  • Advise commencing pubertal induction in girls with hypogonadism around 11-12 years old.
  • Gonadotropin therapy or pulsatile gonadotropin-releasing hormone can be used for treatment of infertility in women and men.
• Management of GH deficiency
  • Offer GH replacement to patients with proven GH deficiency and no contraindications. Recommended starting dose is (Strong recommendation):
    • 0.2-0.4 mg/day for patients < 60 years old
    • 0.1-0.2 mg/day for patients > 60 years old
  • Titrate GH doses and maintain insulin growth factor-1 levels below the upper limit of normal, and reduce the dose if side effects manifest (Strong recommendation).
• Management of antidiuretic hormone deficiency
  • Consider an individualized therapeutic schedule for desmopressin (DDAVP), a synthetic analogue of arginine vasopressin.
  • Desmopressin should ideally be initiated at bedtime, but some patients may also require morning (twice daily) and, rarely, midday (3 times daily) doses.
  • To reduce hyponatremia, educate all patients receiving DDAVP about the risks of overdosing.